Is CLCA2 p.Ala334Asp (c.1001C>A) pathogenic?

CLCA2 p.Ala334Asp (c.1001C>A) is classified Uncertain significance in CLCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely pathogenic (0.5922); Ultra-rare (popmax 0.06%, afr).

How common is CLCA2 p.Ala334Asp (c.1001C>A) in the general population?

CLCA2 p.Ala334Asp (c.1001C>A) is ultra-rare (popmax 0.06%, afr) (gnomAD).

What do computational predictors say about CLCA2 p.Ala334Asp (c.1001C>A)?

AlphaMissense predicts likely pathogenic (score 0.5922) — an in-silico prediction, not a clinical call.

CLCA2 p.Ala334Asp

c.1001C>A · VCV4229414

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5922 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.06%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5922	likely pathogenic · top 8% in CLCA2
REVEL	0.5	indeterminate
SaProt	LLR -14.32	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 31 kb · p 0.29 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.06% African / African-American · 45/75,024 alleles

Filtering AF 0.046% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0411%

Overall 0.00328% 53/1,614,058 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.06%	1,667
East Asian	0.00669%	14,959
Admixed American	0.005%	20,003
Remaining individualsnot grpmax-eligible	0.0032%	31,252

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CLCA2
Protein: p.Ala334Asp
Coding: c.1001C>A
MANE Select: NM_006536
Type: single nucleotide variant
Location: chr1:86438904 (GRCh38)
Gene constraint: LOEUF 1.144 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.87
Residue 334: the vwfa domain

Full CLCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCA2 p.Ala334Gly Uncertain significance ★ ⚠ same residue
CLCA2 p.Leu169Phe Uncertain significance ★★ ⚠ same type
CLCA2 p.Gln842= Benign ★★ same type
CLCA2 p.Thr845= Benign ★★ same type
CLCA2 p.Tyr155= Benign ★★ same type
CLCA2 c.475+2T>A Uncertain significance ★ same type
CLCA2 p.Ala109Val Uncertain significance ★ same type
CLCA2 p.Ala238Val Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/clca2-p-ala334asp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown